The goal of the proposed studies is to address fundamental processes underlying the changes in neuronal excitability in the female brain during periods of altered steroid hormone levels. We will explore the mechanisms governing changes in GABAergic inhibition during the ovarian cycle, pregnancy, and during the interaction between stress and the ovarian cycle. Our experiments will focus on the regulation of GABAAR expression and function by progesterone and its neurosteroid metabolites. We recently demonstrated dynamic, ovarian cycle-linked modifications in specific GABAAR expression and function, while others have shown the same receptors to parallel ovarian cycle changes in the periaqueductal grey matter or to be upregulated in a steroid withdrawal model of PMS. During diestrus in mice when levels of progesterone and of progesterone-derivatives neurosteroids are elevated, there is an increased expression: of the GABAAR 6 subunits in hippocampal neurons and an increase in GABAAR 6 subunit-mediated tonic inhibition in dentate gyrus granule cells (DGGCs). This increase in GABAAR 6 subunits corresponds to a period of lowered seizure susceptibility and anxiety. The specific aims of this project will extend these Findings to the study of GABAAR alterations during pregnancy/postpartum and to the interactions between stress and the ovarian cycle. The fractional contributions of progesterone and its derivatives to the regulation of GABAAR expression and function will be addressed and possible molecular mechanisms (local receptor synthesis and receptor internalization) underlying the changes affecting the GABAergic system will be studied. A novel mouse model of postpartum depression will constitute a unique opportunity to begin to study fundamental neuronal mechanisms underlying this psychiatric disorder affecting nearly 10% of women in early motherhood. Our general hypothesis is that physiological and pathological changes in endogenous steroid hormones in the female brain alter neuronal excitability by producing hormonal state-dependent changes in specific neurotransmitter receptor systems. The focus of the present proposal is GABAergic inhibition in general, and specifically the tonic inhibition mediated by 6 subunit-containing GABAARs, which are the preferred, if not the sole, site mediating neurosteroid sensitivity in the CNS. The project will address the role of endogenous progesterone in GABAAR expression and function in female mice and will identify mechanisms underlying steroid hormone-linked changes in GABAARs by using a variety of molecular biological, biochemical, electrophysiological and behavioral approaches. Our studies are relevant to understanding the pathology of several psychiatric and neurological disorders including pre-menstrual dysphoric disorder (PMDD), catamenial epilepsy, and postpartum depression that are all linked to alterations in hormone levels in women. Uncovering events controlling the hormone-mediated regulation of GABAARs in females will lead to novel and potentially more effective therapeutic targets for treating and ultimately preventing these neurological and psychiatric disorders, while opening the way for fresh approaches to functional and clinical studies in humans.